Discussion
Development of gastric MALT lymphoma appears to arise from two distinct pathways both involving dysregulation of nuclear factor kappa light chain enhancer of activated B-cells (NF-kB) activity.7There is a B-Cell receptor (BCR) dependent NF-kB activation pathway and BCR-independent NF-kB activation pathway.7,8 BCR dependent NF-kB activation relies on persistent antigen stimulation which elicits inflammation and accelerated lymphoid proliferation through a polyclonal B-cell response.7,9,10 This pathway is also recognized as an anti-microbial responsive lymphoid proliferation as when the stimulating antigen is removed, the inflammation and lymphoid proliferation resolves.11The above mechanism is further supported by the effectiveness of eradication therapy in the treatment of H. pylori associated MALT lymphoma. Current literature suggests regression in up to 83% ofH. pylori associated MALT lymphoma cases when given triple or quadruple therapy.12,13
Though uncommon, there are reports showing H. pylori negative MALT lymphoma similar to our case presented above. The predominating theory suggests a BCR-independent NF-kB activation pathway. Though there is a clear theory describing the pathway for lymphoid proliferation inH. pylori negative patients, the exact mechanism is yet to be determined and is likely multifactorial. One known etiology is a pseudo-negative H. pylori associated MALT lymphoma. In these patients, H. pylori testing is negative due to previous use of antibiotics, bismuth, proton pump inhibitors (PPIs), or a combination of the three despite active infection with H. pylori .14 Some studies indicate t certain chromosomal translocations or tumor suppression gene mutations can cause constitutive lymphoid proliferation independent of a stimulating antigen.15 Multiple publications demonstrate a high incidence of translocation (11;18)(Q21;Q21) in H. pylori negative MALT lymphomas.7,16-18 These translocations cause a fusion of the N-terminus of the API2 gene to the C-terminus of the MALT1 gene and generates a functional API2–MALT1 fusion product which can constitutively activate the NF-kB pathway.19
Presence of the t(11;18)(q21:q21) is seen in up to 30% of all gastric MALT lymphomas and are demonstrated in up to 68% that are at stage IIE or above.20 Unfortunately, the current available data has not closely evaluated the incidence of these translocations in patients with H. pylori negative gastric MALT lymphoma, though there are multiple studies that show expression of these translocations in up to 88% of these patients.7,16-20 Regardless, the presence of t(11;18)(q21:q21) can help guide therapy as they are only seen in approximately 3% of gastric MALT lymphomas that do respond to traditional H. pylori eradication therapy.20Further studies noted that the presence of t(11;18)(q21:q21) predicted poor response to alkylating agents (chlorambucil or cyclophosphamide) but was unable to predict the response to rituximab.21,22
Treatment of patients with H. pylori negative MALT lymphoma is complicated and differs depending upon the patient’s comorbidities, staging, and the presence or absence of translocations. Current literature suggests using radiation therapy for patients with early stage (Lugano I/II) gastric MALT lymphoma without evidence of H. pylori infection and reported clinical remission rates in up to 100% of patients.23,24 If radiation therapy fails or the patient is found to be at an advanced stage, treatment with immunotherapy (Rituxumab) can be trialed and has shown complete response in up to 46% of patients.22,25 Prior to discovery the of H. pylori , targeted gastric resection was used to great therapeutic effect and long term survival.22,26However, more recent studies suggest that organ conserving therapy presents no long-term disadvantages but spares the patient from permanent nutritional and metabolic derangements.27For these reasons, surgical treatment of gastric MALT lymphoma is rarely pursued.
In the case above, testing for t(11;18)(q21:q21) was negative. Rituximab was preferred over radiation therapy in our patient with history of systemic sclerosis but was ineffective.. She has shown endoscopic and histologic improvement with radiation therapy with 3 month repeat follow up endoscopy pending.
In conclusion, H. pylori negative gastric lymphoma of MALT type is an uncommon presentation of non-Hodgkin lymphoma. Though the mechanism appears well researched, the specific etiology remains controversial. In patients with gastric lymphoma of MALT type, it is important to rule out H. pylori infection. If negative, further evaluation of the t(11;18)(q21:q21) can help further guide therapy and predict patient outcomes. Lastly, MALT lymphoma in patients that have undergone Roux-en-Y gastric bypass is uncommon with less than 40 cases in the reported literature. Thus diagnosis can be delayed due to mimicking symptoms typically attributed to the bypass. Evaluation, not only of the gastric pouch, but also the gastric remnant should be performed in all at risk patients as gastric MALT lymphoma can occur in both locations despite post-operative anatomical separation.
The authors confirm contribution to the paper as follows:
Study conception and design: Zachary R Eagle MD1; Francis Essien DO1; Kimberly Zibert DO2; Charles Miller MD2; Rina Eden DO3; Ross Pinson MD1,4
Data collection Zachary R Eagle MD1; Rina Eden DO3; Ross Pinson MD1,4
Analysis and interpretation of results: Zachary R Eagle MD1; Kimberly Zibert DO2; Charles Miller MD2; Rina Eden DO3; Ross Pinson MD1,4
Draft manuscript preparation: Zachary R Eagle MD1; Francis Essien DO1; Ross Pinson MD1,4
All authors discussed the results and contributed to the final manuscript.
Data sharing is not applicable to this article as no new data were created or analyzed in this study.